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Open Access Highly Accessed Research article

Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells

Yong Zhao1*, Zhaoshun Jiang2, Tingbao Zhao3, Mingliang Ye4, Chengjin Hu5, Zhaohui Yin2, Heng Li6, Ye Zhang7, Yalin Diao4, Yunxiang Li4, Yingjian Chen5, Xiaoming Sun5, Mary Beth Fisk8, Randal Skidgel9, Mark Holterman10, Bellur Prabhakar11 and Theodore Mazzone1

Author Affiliations

1 Section of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL 60612 USA

2 Section of Endocrinology, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China

3 Stem Cell Treatment Center, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China

4 Section of Blood Transfusion, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China

5 Section of Molecular Diagnostics, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China

6 Section of Neuronology, Jinan Central Hospital, 105 Jiefang Road, Jinan, Shandong 250020, P.R. China

7 Jinan Tianhe Stem Cell Biotechology Co. Ltd., 750 Shunhua Road, Jinan, Shandong 250055, P.R. China

8 Texas Cord Blood Bank, 6211 IH-10 West, San Antonio, TX 78201 USA

9 Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612 USA

10 Department of Surgery, University of Illinois at Chicago, 420 NE GLen Oak, Suite 201, Peoria, IL 61603 USA

11 Department of Immunology and Microbiology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612 USA

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BMC Medicine 2012, 10:3  doi:10.1186/1741-7015-10-3

Published: 10 January 2012

Abstract

Background

Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.

Methods

We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21).

Results

Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6) and patients with no residual pancreatic islet β cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.

Conclusions

Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.

Trial registration

ClinicalTrials.gov number, NCT01350219.